How Should the FDA Regulate Fecal Transplantation Safely and Effectively?

This post written by Rachel Sachs originally appeared in the Bill of Health blog.

A draft version of the paper referred to in this blog post, co-authored by Sachs and Edelstein, is now available here.

[An early December] issue of the New Yorker featured a terrific article about fecal microbiota transplantation, or FMT.  Much of the article focused on OpenBiome, a nonprofit stool bank spun off from MIT that screens donors, processes samples, and ships them to hospitals around the country.  For those who are unfamiliar with FMT, it is a startlingly effective treatment for recurrent C. difficile infection.  C. diff infections have become among the most common hospital-acquired infections in the United States, causing more than 300,000 hospitalizations and 14,000 deaths annually.  And unfortunately, many of these infections are resistant to antibiotics, with resistance rates rising rapidly.  But FMT may provide a way forward: a recent randomized trial (antibiotics versus antibiotics plus FMT) was stopped early, when 94% of patients in the FMT group were cured, as compared to roughly 30% of those in the antibiotics groups.

Coincidentally, I’ve been working with OpenBiome over the past few months on an interesting question that the New Yorker article touched on only briefly: how should the FDA regulate FMT to best ensure its safety and efficacy?  At present, the FDA is proposing to regulate FMT as a biologic drug.  However, many (including OpenBiome’s co-founder, Mark Smith) have argued that it ought to be regulated like human tissue, which from a scientific standpoint it resembles more closely than it does a small molecule drug, given the challenge of characterizing stool’s active ingredients and providing consistency across batches.  OpenBiome’s Policy Director, Carolyn Edelstein, and I are currently working on a paper examining the pluses and minuses of the FDA’s current approach.  I want to briefly summarize a few key points of our paper here, but essentially we argue that classifying FMT as a drug is simultaneously underregulatory and overregulatory.  Our primary goal is to ensure that patients have access to safe, effective treatments – and that means the FDA should be more involved in regulating some aspects of FMT, and less involved in others.

Underregulation: As the FDA oversees the clinical trial system, it is generally concerned about two key metrics: the compound’s safety and its efficacy.  It does not, however, prioritize the safety of the process by which the compound is produced and stored.  Yet it is precisely that process which is critical in the case of FMT.  Much like the way the FDA has codified its regulations around blood or tissue, there is a strong need for regulations specifying who may donate stool, what pathogens it must be screened for, how it must be stored and shipped, etc.  The FDA has given no indication that it plans to issue such regulations, but given the known risks of pathogen transmission through stool, it should act to do so.  Professional societies have stepped in with “best practice” guidelines, but these should be formalized at the federal level.

Overregulation: At the same time, regulating FMT as a drug would also be overregulatory, specifically in the context of treating recurrent C. diff infection.  Scientists have already performed clinical trials evaluating the efficacy of FMT as a treatment for recurrent C. diff, with such strong effect sizes that completing large trials was not necessary for establishing efficacy.  What is needed, though, is information about its efficacy for other disorders (the New Yorker article mentions Crohn’s disease as one possible indication).  Regulating FMT as a drug might have the perverse effect of delaying the gathering of that information.  Currently, the FDA is exercising its enforcement discretion and has chosen to allow doctors to prescribe FMT, but only for recurrent C. diff.  However, multiple companies have submitted Investigational New Drug (IND) applications covering FMT for the treatment of recurrent C. diff and are proceeding through the clinical trial process.  If approved, a processing company could then provide its stool off label for all indications, dampening the incentive to perform further clinical trials.  (Granting biologic or orphan drug exclusivity to a single company also has safety ramifications, as we address in the piece, due to the do-it-yourself potential of FMT.)

Yet the FDA has a way out of this problem: it could adopt a hybrid approach, in which it regulates FMT differently depending on the disease it’s intended to treat.  Due to similar concerns, the FDA has adopted this modality for regulating cord blood.  Where banked cord blood is intended for later use by its donor or that donor’s close relatives, that cord blood is regulated as a biological product, in a way that prioritizes the safety of the donation and storage process.  But where blood is intended for use by a patient unrelated to the donor, it is regulated both as a biological product and as a drug.  This means that those seeking to use cord blood for alternative purposes must also submit an IND for the requested indication, a process which might involve extensive clinical trials.  Adopting this approach would permit the FDA to regulate different indications of FMT differently, depending on whether efficacy has been proven in a particular case.  The FDA should strongly consider this more tailored approach.

Rachel Sachs is an Academic Fellow at the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School.

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